Systemic hypoxia evokes a series of neural, humoral and direct cellular effects that act to preserve oxygen (O2) delivery to metabolically active tissues. In human skeletal muscle vasodilation occurs during systemic hypoxia despite a substantial increase in sympathetic nerve traffic. This vasodilation has been attributed to local release of vasodilator metabolites such as adenosine, nitric oxide (NO) and/or prostaglandins. The precise mechanism of hypoxia-induced skeletal muscle vasodilation in humans, the source of the vasodilator metabolites and their interaction with the sympathetic nervous system are poorly understood. The principal hypothesis of this proposal is that during systemic hypoxia, neural vasoconstrictor influences are offset by the peripheral production of vasodilator substances resulting in functional sympatholysis. In this project we propose to address four specific aims. We hypothesize that: 1) Adenosine and NO are released during systemic hypoxia in skeletal muscle and cause vasodilation; 2) Systemic hypoxia leads to release of prostaglandins that contribute to skeletal muscle vasodilation; 3) K + (ATP) channels are important mediators of skeletal muscle vasodilation induced by metabolites that are released during hypoxia; and, 4) Cellular/tissue metabolites produced during systemic hypoxia interfere with sympathetic neural vasoconstriction. The site of this interference is not known. These hypotheses will be tested in conscious humans and with the use of a series of state-of-the-art experimental techniques. We will use microneurography to measure peripheral sympathetic nerve activity (the neural vasoconstrictor signal), intramuscular and intravascular microdialysis to measure sympathetic neurotransmitters and vasoactive metabolites (the chemical vasomotor signals) and ultrasound/plethysmography to measure blood flow (the target organ effect). A number of pharmacological probes will be applied to interfere specifically with hypoxia-induced vasodilation. The scientific concepts developed and the experimental approaches planned in this proposal will be enhanced importantly by the collective expertise of the investigators on this Program Project Grant. Because sympathetic and vascular function may be altered importantly by disease and/or by aging, the findings of these studies may have important clinical implications.